OBJECTIVES: Epidemiological studies documented associations between single nucleotide polymorphisms (SNPs) in the nucleotide excision repair gene XPD/ERCC2 and cancer risk. Little is known, however, about the underlying mechanisms for these associations. We explored a novel mechanism that could further explain the reported risk-modifying effect of these SNPs on disease susceptibility. METHODS: Using quantitative real-time polymerase chain reaction, we examined the relationship between three SNPs in the XPD gene (R156R in exon 6, D312N in exon 10 and K751Q in exon 23) and mRNA levels as a potential mechanism by which these SNPs could alter DNA repair capacity and affect disease risk. To further investigate the mechanism(s) by which these SNPs alter mRNA transcription levels, we performed a localized Mfold structure analysis on the mRNA sequence surrounding the studied SNPs. RESULTS: All three SNPs studied, alone and in combination, significantly decreased constitutive XPD mRNA levels (P<0.003) in lymphocytes of healthy subjects. The decrease in mRNA levels was significantly greater in smokers and was exacerbated by smoking duration and intensity. The decrease was more pronounced in older than in younger subjects. The R156R and the K751Q polymorphisms were predicted to alter mRNA secondary structure, indicating that these SNPs potentially affect local folding and mRNA stability. CONCLUSIONS: Our results provide novel mechanistic explanations for epidemiological studies linking these SNPs to elevated cancer risk and emphasize the importance of comprehensively investigating the effect of both synonymous and nonsynonymous SNPs as risk modifiers by considering their potential effects on gene expression, protein translation and functions. © 2007 Lippincott Williams & Wilkins, Inc.